Tertiary alcohols alkylation

Another method for the conversion of alkyl hahdes to carboxylic esters is treatment of a halide with nickel carbonyl Ni(CO)4 in the presence of an alcohol and its conjugate base. When R is primary, RX may only be a vinylic or an aryl halide retention of configuration is observed at a vinylic R. Consequently, a carbocation intermediate is not involved here. When R is tertiary, R may be primary alkyl as well as vinylic or aryl. This is thus one of the few methods for preparing esters of tertiary alcohols. Alkyl iodides give the best results, then bromides. In the presence of an amine, an amide can be isolated directly, at least in some instances. 

Because of the low reactivity of the tertiary alcohol, alkylation of the 014-hydroxyl with alkyl halides such as propyl or isoamyl halides was unsuccessful [Schmidhammer H, unpublished observations]. Therefore, allylic halides were employed to introduce 14-O-alkenyl substituents using similar conditions as described above [ 43—461. Catalytic hydrogenation afforded the corresponding 14-O-alkyl derivatives [43 -5]. Thus, 14-hydroxy-5-methylcodeinone (20) was treated with 3,3-dimethylallyl bromide in DMF in the presence of NaH to give compound 21, which underwent catalytic hydrogenation to yield 14-O-isoamyl-substituted morphinan 24 (Scheme 5) [43]. Similarly 14-phenylpropoxymorphinans 25 and 26 were prepared from 14-hydroxycodeinone (3) and 21, respectively, via intermediates 22 and 23, which were obtained by alkenylation using cinnamyl bromide (Scheme 5) [44, 45],... 

The resulting esters differ sufficiently in odour and water solubility to be readily distinguished from the original alcohol. With tertiary alcohols the product is largely the alkyl chloride ... 

Alcohols and alkyl halides are classified as primary secondary or tertiary according to the degree of substitution of the carbon that bears the functional group (Section 2 13) Thus primary alcohols and primary alkyl halides are compounds of the type RCH2G (where G is the functional group) secondary alcohols and secondary alkyl halides are compounds of the type R2CHG and tertiary alcohols and tertiary alkyl halides are com pounds of the type R3CG... 

The order of reactivity of the hydrogen halides parallels their acidity HI > HBr > HCl >> HF Hydrogen iodide is used infrequently however and the reaction of alco hols with hydrogen fluoride is not a useful method for the preparation of alkyl fluorides Among the various classes of alcohols tertiary alcohols are observed to be the most reactive and primary alcohols the least reactive... 

Tertiary alcohols are converted to alkyl chlorides m high yield within minutes on reaction with hydrogen chloride at room temperature and below... 

Because tertiary alcohols are so readily converted to chlorides with hydrogen chlo nde thionyl chlonde is used mainly to prepare pnmary and secondary alkyl chlondes Reactions with thionyl chlonde are normally carried out m the presence of potassium carbonate or the weak organic base pyndme... 

The rate at which alcohols are converted to alkyl halides depends on the rate of carbocation formation tertiary alcohols are most reactive primary alcohols and methanol are least reactive... 

Additional evidence for carbocation intermediates in certain nucleophilic substitutions comes from observing rearrangements of the kind normally associated with such species For example hydrolysis of the secondary alkyl bromide 2 bromo 3 methylbutane yields the rearranged tertiary alcohol 2 methyl 2 butanol as the only substitution product... 

With secondary and tertiary alcohols Ihis slage is an 8 1 reaclion m which Ihe alkyl oxonium ion dissociates to a carbocalion and water... 

The few studies that have been carried out with optically active tertiary alcohols indicate that almost complete racemization accompanies the preparation of tertiary alkyl halides by this method... 

Unbranched primary alcohols and tertiary alcohols tend to react with hydrogen halides without rearrangement The alkyloxonmm ions from primary alcohols react rap idly with bromide ion for example m an Sn2 process Tertiary alcohols give tertiary alkyl halides because tertiary carbocations are stable and show little tendency to rearrange... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

Moderate yields of acids and ketones can be obtained by paHadium-cataly2ed carbonylation of boronic acids and by carbonylation cross-coupling reactions (272,320,321). In an alternative procedure for the carbonylation reaction, potassium trialkylborohydride ia the presence of a catalytic amount of the free borane is utilized (322). FiaaHy, various tertiary alcohols including hindered and polycycHc stmctures become readily available by oxidation of the organoborane iatermediate produced after migration of three alkyl groups (312,313,323). 

Alkyl boric acid esters derived from straight-chain alcohols and aryl boric acid esters are stable to relatively high temperatures. Methyl borate is stable to 470°C (11). Trialkoxyboranes from branched-chain alcohols are much less stable, and boranes from tertiary alcohols can even decompose at 100°C (12). Decomposition of branched-chain esters leads to mixtures of olefins, alcohols, and other derivatives. 

AsH, primary and secondary amines, and lower alcohols, BCl, BBr, and BI react to hberate the corresponding hydrogen hahde. Tertiary alcohols and the boron tnhahdes yield the alkyl hahde and boric acid. The boron tnhahdes hydrolyze readily in water or moist air to produce boric acid and hydrogen hahdes. 

Almost 40 years later the Lummus Co. patented an integrated process involving the addition of chlorine along with the sodium chloride and sodium hydroxide from the cathode side of an electrolytic cell to a tertiary alcohol such as tertiary butanol to produce the tertiary alkyl hypochlorite. The hypochlorite phase separates, and the aqueous brine solution is returned to the electrolytic cells. The alkyl hypochlorite reacts with an olefin in the presence of water to produce a chlorohydrin and the tertiary alcohol, which is returned to the chlorinator. With propylene, a selectivity to the chlorohydrin of better than 96% is reported (52). A series of other patents covering this technology appeared during the 1980s (53—56). 

Phenyl isocyanates are generally more reactive than alkyl isocyanates in their reactions with alcohols, but with CuCl catalysis even alkyl isocyanates will react readily with primary, secondary, or tertiary alcohols (45-95% yield). ... 

The rearrangement of an ether 1 when treated with a strong base, e.g. an organo-lithium compound RLi, to give an alcohol 3 via the intermediate a-metallated ether 2, is called the Wittig rearrangement. The product obtained is a secondary or tertiary alcohol. R R can be alkyl, aryl and vinyl. Especially suitable substrates are ethers where the intermediate carbanion can be stabilized by one of the substituents R R e.g. benzyl or allyl ethers. 

Alkylation of these as their sodium salts with the ubiquitous N-C2-chloroethyl)dimethylamine affords the desired antihistamines. There are thus obtained, respectively, mephenhydramine (23a) chlorphenoxamine (23b), and mebrophenhydramine (23c)Alkylation of the tertiary alcohol, 22b, with the pyrrolidine derivative, 24, affords meclastine (25). In much the same vein, reaction of 2-acetylpyridine with phenyImagnesium bromide gives the tertiary alcohol, 27. Alkylation in the usual way leads to the potent antihistamine, doxylamine (28). " ... 

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